Multiplexed noninvasive analyzer apparatus and method of use thereof

ABSTRACT

A noninvasive analyzer apparatus and method of use thereof is described using a plurality of time resolved sample illumination zones coupled to at least one two-dimensional detector array monitoring a plurality of detection zones. Control of illumination times and/or patterns along with selected detection zones yields pathlength resolved groups of spectra. Sectioned pixels and/or zones of the detector are optionally filtered for different light throughput as a function of wavelength. The pathlength resolved groups of spectra are subsequently analyzed to determine an analyte property. Optionally, in the mapping and/or collection phase, incident light is controllably varied in time in terms of any of: sample probe position, incident light solid angle, incident light angle, depth of focus, energy, intensity, and/or detection angle. Optionally, one or more physiological property and/or model property related to a physiological property is used in the analyte property determination.

CROSS REFERENCES TO RELATED APPLICATIONS

This application:

-   -   is a continuation-in-part of U.S. patent application Ser. No.         13/941,411 filed Jul. 12, 2013, which is a continuation-in-part         of U.S. patent application Ser. No. 13/941,389 filed Jul. 12,         2013, which is a continuation-in-part of U.S. patent application         Ser. No. 13/941,369 filed Jul. 12, 2013, which claims the         benefit of:         -   U.S. provisional patent application No. 61/672,195 filed             Jul. 16, 2012;         -   U.S. provisional patent application No. 61/700,291 filed             Sep. 12, 2012; and         -   U.S. provisional patent application No. 61/700,294 filed             Sep. 12, 2012; and     -   claims the benefit of U.S. provisional patent application No.         61/845,926 filed Jul. 12, 2013,     -   all of which are incorporated herein in their entirety by this         reference thereto.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a noninvasive analyzer using a sample mapping phase to generate instrumentation setup parameters followed by a subject specific data collection phase using the configured instrument.

DESCRIPTION OF THE RELATED ART

Patents and literature related to the current invention are summarized herein.

Diabetes

Diabetes mellitus or diabetes is a chronic disease resulting in the improper production and/or use of insulin, a hormone that facilitates glucose uptake into cells. Diabetes is broadly categorized into four forms grouped by glucose concentration state: hyperinsulinemia (hypoglycemia), normal physiology, impaired glucose tolerance, and hypoinsulinemia (hyperglycemia).

Diabetics have increased risk in three broad categories: cardiovascular heart disease, retinopathy, and/or neuropathy. Complications of diabetes include: heart disease, stroke, high blood pressure, kidney disease, nerve disease and related amputations, retinopathy, diabetic ketoacidosis, skin conditions, gum disease, impotence, and/or fetal complications.

Diabetes is a common and increasingly prevalent disease. Currently, diabetes is a leading cause of death and disability worldwide. The World Health Organization estimates that the number of people with diabetes will grow to three hundred million by the year 2025.

Long term clinical studies show that the onset of diabetes related complications is significantly reduced through proper control of blood glucose concentrations, The Diabetes Control and Complications Trial Research Group, “The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus”, N. Eng. J. of Med., 1993, vol. 329, pp. 977-986.

Skin

The structure of skin varies widely among individuals as well as between different skin sites on a single individual. The skin has layers, including: (1) a stratum corneum of flat, dehydrated, biologically inactive cell about 10 to 20 micrometers thick; (2) a stratified epidermis, of about 10 to 150 micrometers thickness, formed and continuously replenished by slow upward migration of keratinocyte cells from the germinative basal layer of the epidermis; (3) an underlying dermis of connective fibrous protein, such as collagen, and a blood supply, which form a layer of 0.5 to 4.0 millimeters in thickness with an average thickness of about 1.2 millimeters; and (4) a underlying fatty subcutaneous layer or adipose tissue.

Fiber Optic Sample Bundle

Garside, J., et. al., “Fiber Optic Illumination and Detection Patterns, Shapes, and Locations for use in Spectroscopic Analysis”, U.S. Pat. No. 6,411,373 (Jun. 25, 2002) describe software and algorithms to design fiber optic excitation and/or collection patterns in a sample probe.

Maruo, K., et. al., “Device for Non-Invasive Determination of Glucose Concentration in Blood”, European patent application no. EP 0843986 B1 (Mar. 24, 2004) described the use of light projecting fiber optics in the range of 0.1 to 2 millimeters from light receiving fiber optics at the contacted fiber optic bundle/sample interface.

Skin Thickness

Rennert, J., et. al., “Non-Invasive Method of Determining Skin Thickness and Characterizing Layers of Skin Tissue In Vivo”, U.S. Pat. No. 6,456,870 B1 (Sep. 24, 2002) described the use of near-infrared absorbance spectra to determine overall thickness of skin tissue and layer-by-layer thickness of skin tissue.

Ruchti, T. L., et. al., “Classification System for Sex Determination and Tissue Characterization”, U.S. Pat. No. 6,493,566 B1 (Dec. 10, 2002) describe the near-infrared tissue measurements to yield predictions consisting of gender and one or more of thickness of a dermis, collagen content, and amount of subcutaneous fat.

Mattu, M., et. al., “Classification and Screening of Test Subjects According to Optical Thickness of Skin”, U.S. Pat. No. 6,738,652 B2 (May 18, 2004) describe the use of near-infrared reflectance measurements of skin to determine the optical thickness of skin through analysis of water, fat, and protein marker bands.

Sample Probe/Tissue Contact

Abul-Haj, A., et. al., “Method and Apparatus for Noninvasive Targeting”, U.S. patent application no. US 2006/0217602 A1 (Sep. 28, 2006) describe a sample probe interface method and apparatus for targeting a tissue depth and/or pathlength that is used in conjunction with a noninvasive analyzer to control spectral variation.

Welch, J. M., et. al., “Method and Apparatus for Noninvasive Probe/Skin Tissue Contact Sensing”, WIPO International publication no. WO 2008/058014 A2 (May 15, 2008) describe a method and apparatus for determining proximity and/or contact of an optical probe with skin tissue.

PROBLEM STATEMENT

What is needed is a noninvasive glucose concentration analyzer having precision and accuracy suitable for treatment of diabetes mellitus.

SUMMARY OF THE INVENTION

The invention comprises a noninvasive analyzer apparatus having an array detector sensing a plurality of detection zones couple to a plurality of illumination zones and a method of use thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete understanding of the present invention is derived by referring to the detailed description and claims when considered in connection with the Figures, wherein like reference numbers refer to similar items throughout the Figures.

FIG. 1 illustrates an analyzer;

FIG. 2 illustrates diffusely reflecting optical paths;

FIG. 3 illustrates probing tissue layers using a spatial distribution method;

FIG. 4 illustrates varying illumination zones relative to a detector;

FIG. 5 illustrates varying detection zones relative to an illuminator;

FIG. 6A illustrates an end view of an array detector and FIG. 6B illustrates a side view of the array detector;

FIGS. 7(A-E) illustrate a coupled source detector array system, FIG. 7A; a side illuminated array detector system, FIG. 7B; a corner illuminated array detector system, FIG. 7C; a within array illumination system, FIG. 7D; and an array illuminated detector array system, FIG. 7E;

FIGS. 8(A-D) illustrate a first example of a multiple two-dimensional array detector system, FIG. 8A; a second example of a multiple two-dimensional array detector system, FIG. 8B; a third example of a multiple two-dimensional array detector system, FIG. 8C; and a fourth example of a multiple two-dimensional array detector system, FIG. 8D;

FIGS. 9(A-D) illustrate temporal resolution gating, FIG. 9A; probabilistic optical paths for a first elapsed time, FIG. 9B; probabilistic optical paths for a second elapsed time, FIG. 9C; and a temporal distribution method, FIG. 9D;

FIGS. 10(A-C) illustrate a fiber optic bundle, FIG. 10A; a first example sample interface end of the fiber optic bundle, FIG. 10B; and a second example sample interface end of the fiber optic bundle, FIG. 10C;

FIG. 11A illustrates a third example sample interface end of the fiber optic bundle and FIG. 11B illustrates a mask;

FIG. 12 illustrates a mask selection wheel;

FIG. 13A illustrates a position selection optic; FIG. 13B illustrates the position selection optic selecting position; FIG. 13C illustrates solid angle selection using the position selection optic; and FIG. 13D illustrates radial control of incident light relative to a detection zone;

FIGS. 14(A-B) illustrate a pathlength resolved sample interface for (1) a first subject, FIG. 14A and (2) a second subject, FIG. 14B;

FIG. 15 provides a method of use of a data processing system; and

FIG. 16 provides a method of using a sample mapping phase and a subsequent subject specific data collection phase.

Elements and steps in the figures are illustrated for simplicity and clarity and have not necessarily been rendered according to any particular sequence. For example, steps that are performed concurrently or in a different order are illustrated in the figures to help improve understanding of embodiments of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention comprises a noninvasive analyzer apparatus and method of use thereof using a plurality of two-dimensional near-infrared detector arrays.

In another embodiment, an apparatus and method of use thereof is described using a plurality of time resolved sample illumination zones coupled to at least one two-dimensional detector array monitoring a plurality of detection zones linked to the sample illumination zones.

In still another embodiment, an apparatus and method of use thereof is described using acquisition of noninvasive mapping spectra of skin and subsequent optical/optical path reconfiguration for subsequent subject specific data collection.

For example, a near-infrared noninvasive analyzer is configured with a first optical configuration used to map an individual and/or group of individuals through use of mapping spectra. The mapping spectra are analyzed and used to reconfigure the optical setup of the analyzer to a second optical configuration suited to the individual and/or group of individuals. Subsequently, collection of noninvasive spectra of the individual and/or group of individuals is performed using the second optical configuration, which is preferably optimized to yield additional information based on the skin of the individual and/or group of individuals.

In yet another embodiment, a data processing system analyzes data from an analyzer to estimate and/or determine an analyte property, such as concentration using multiple types of data, such as from an external sensor, from two or more radial positions, and/or with two of more focusing depths.

In still another embodiment, an analyzer using light interrogates the sample using one or more of:

-   -   a spatially resolved system;         -   an incident light radial distance resolved system;         -   a controllable and variable incident light solid angle             system; and         -   a controllable and variable incident light angle system;     -   a time resolved system, where the times are greater than about         1, 10, 100, or 1000 microseconds;     -   a picosecond timeframe resolved system, where times are less         than about 1, 10, 100, or 1000 nanoseconds;     -   collection of spectra with varying radial distances between         incident light entering skin and detected light exiting the         skin;     -   an incident angle resolved system; and     -   a collection angle resolved system.

Data from the analyzer is analyzed using a data processing system capable of using the information inherent in the resolved system data.

In yet another embodiment, a data processing system uses interrelationships of chemistry based a-priori spectral information related to absorbance of a sample constituent and/or the effect of the environment, such as temperature, on the spectral information.

In yet still another embodiment, a data processing system uses a first mapping phase to set instrument control parameters for a particular subject, set of subjects, and/or class of subjects. Subsequently, the control parameters are used in a second data collection phase to collect spectra of the particular subject or class of subjects.

In still yet another embodiment, a data processing system uses information related to contact pressure on a tissue sample site.

In another embodiment, a data processing system uses a combination of any of:

-   -   spatially resolved information;     -   temporally resolved information on a time scale of longer than         about one microsecond;     -   temporally resolved information on a sub one hundred picosecond         timeframe;     -   incident photon angle information;     -   photon collection angle information;     -   interrelationships of spectral absorbance and/or intensity         information;     -   environmental information;     -   temperature information; and     -   information related to contact pressure on a tissue sample site.

In still yet another embodiment, a temporal resolution gating noninvasive analyzer is used to determine an analyte property of a biomedical sample, such as a glucose concentration of a subject using light in the near-infrared region from 1000 to 2500 nanometers.

Axes

Herein, axes systems are separately defined for an analyzer and for an interface of the analyzer to a patient, where the patient is alternatively referred to as a subject.

Herein, when referring to the analyzer, an x, y, z-axes analyzer coordinate system is defined relative to the analyzer. The x-axis is the in the direction of the mean optical path. The y-axis crosses the mean optical path perpendicular to the x-axis. When the optical path is horizontal, the x-axis and y-axis define a x/y horizontal plane. The z-axis is normal to the x/y plane. When the optical path is moving horizontally, the z-axis is aligned with gravity, which is normal to the x/y horizontal plane. Hence, the x, y, z-analyzer coordinate system is defined separately for each optical path element. If necessary, where the mean optical path is not horizontal, the optical system is further defined to remove ambiguity.

Herein, when referring to the patient, an x, y, z-axes patient coordinate system is defined relative to a body part interfaced to the analyzer. Hence, the x, y, z-axes body coordinate system moves with movement of the body part. The x-axis is defined along the length of the body part, the y-axis is defined across the body part. As an illustrative example, if the analyzer interfaces to the forearm of the patient, then the x-axis runs longitudinally between the elbow and the wrist of the forearm and the y-axis runs across the forearm. Together, the x,y plane tangentially touches the skin surface at a central point of the interface of the analyzer to the body part, which is referred to as the center of the sample site, sample region, or sample site. The z-axis is defined as orthogonal to the x,y plane. Rotation of an object is further used to define the orientation of the object to the sample site. For example, in some cases a sample probe of the analyzer is rotatable relative to the sample site. Tilt refers to an off z-axis alignment, such as an off z-axis alignment of a probe of the analyzer relative to the sample site.

Analyzer

Referring now to FIG. 1, an analyzer 100 is illustrated. The analyzer comprises at least: a light source system 110, a photon transport system 120, a detector system 130, and a data processing system 140. In use the analyzer 100 estimates and/or determines a physical property, a sample state, a constituent property, and/or a concentration of an analyte.

Patient/Reference

Still referring to FIG. 1, an example of the analyzer 100 is presented. In this example, the analyzer 100 includes a sample interface 150, which interfaces to a reference material 160 and/or to a subject 170. Herein, for clarity of presentation a subject 170 in the examples is representative of a person, animal, a prepared sample, and/or patient. In practice, the analyzer 100 is used by a user to analyze the user, referred to as the subject 170, the subject 170 and is used by a medical professional to analyze a patient.

Controller

Still referring to FIG. 1 and referring now to FIG. 5, the analyzer 100 optionally includes a system controller 180. The system controller 180 is used to control one or more of: the light source system 110 or a light source 112 thereof, the photon transport system 120, the detector system 130 or a detector 132 thereof, the sample interface 150, position of the reference 160 relative to the sample interface 150, position of the subject 170 relative to the sample interface 150, and communication to an outside system 190, such as a personal communication device 192, a smart phone, and/or a remote system 194 using a wireless communication system 196 and/or hard wired communication system 198. For example, the remote system includes a data processing system, a data storage system, and/or a data organization system.

Still referring to FIG. 1, the optional system controller 180 operates in any of a predetermined manner or in communication with the data processing system 140. In the case of operation in communication with the data processing system 140, the controller generates control statements using data and/or information about the current state of the analyzer 100, current state of a surrounding environment 162 outside of the analyzer 100, information generated by the data processing system 140, and/or input from a sensor, such as a sample interface sensor 152 or an auxiliary system 10 or an auxiliary sensor 12 thereof. Herein, the auxiliary system 10 is any system providing input to the analyzer 100.

Still referring to FIG. 1, the optional system controller 180 is used to control: photon intensity of photons from the source using an intensity controller 122, wavelength distribution of photons from the source 110 using a wavelength controller 124, and/or physical routing of photons from the source 110 using a position controller 126.

Still referring to FIG. 1, for clarity of presentation the optional outside system 190 is illustrated as using a smart phone 192. However, the smart phone 192 is optionally a cell phone, a tablet computer, a computer network, and/or a personal computer. Similarly, the smart phone 192 also refers to a feature phone, a mobile phone, a portable phone, and/or a cell phone. Generally, the smart phone 192 includes hardware, software, and/or communication features carried by an individual that is optionally used to offload requirements of the analyzer 100. For example, the smart phone 192 includes a user interface system, a memory system, a communication system, and/or a global positioning system. Further, the smart phone 192 is optionally used to link to the remote system 194, such as a data processing system, a medical system, and/or an emergency system. In another example at least one calculation of the analyzer in noninvasively determining a glucose concentration of the subject 170 is performed using the smart phone 192. In yet another example, the analyzer gathers information from at least one auxiliary sensor 12 and relays that information and/or a processed form of that information to the smart phone 192, where the auxiliary sensor is not integrated into the analyzer 100. Optionally data from the analyzer 100 is processed in the cloud. Optionally, the smart phone 192 is used as a portal between the analyzer 100 and the cloud.

Source

Herein, the source system 110 generates photons in any of the visible, infrared, near-infrared, mid-infrared, and/or far-infrared spectral regions. In one case, the source system generates photons in the near-infrared region from 1100 to 2500 nm or any range therein, such as within the range of about 1200 to 1800 nm; at wavelength longer than any of 800, 900, 1000, and 1100 nm; and/or at wavelengths shorter than any of 2600, 2500, 2000, or 1900 nm.

Photon/Skin Interaction

Light interacts with skin through laws of physics to scatter and transmit through skin voxels also referred to as volume pixels.

Referring now to FIG. 2, for clarity of presentation and without limitation, in several examples provided herein a simplifying and non-limiting assumption is made, for some wavelengths, for some temperatures, and for some optical configurations, that a mean photon depth of penetration increases with mean radial distance between a photon illumination zone and a photon detection zone. For example, for photons transmitting from a sample illumination zone, through the subject, and through a photon detection zone, such as at a subject/analyzer interface:

-   -   at a first radial distance, photons penetrate with a mean         maximum depth of penetration into an epidermal layer of a         subject;     -   at a second larger radial distance, photons penetrate with a         mean maximum depth of penetration into a dermal layer of the         subject; and     -   at a third still larger radial distance, photons penetrate with         a mean maximum depth of penetration into a subcutaneous fat         layer of the subject.

Referring still to FIG. 2 and referring now to FIG. 5, a photon transit system 200 through skin layers of the subject 170 is illustrated. In this example, the photon transport system 120 guides light from a source 112 of the source system 110 to the subject 170, optionally with an air gap 210 between a last optic of an illumination system and skin of the subject 170. Further, in this example, the photon transport system 120 irradiates skin of the subject 170 over a narrow illumination zone, such as having an area of less than about 9, 4, 1, 0.25, 0.1, and/or 0.01 mm². Optionally, the photons are delivered to the skin of the subject 170 through an optic proximately contacting, but not actually contacting, the skin, such as within about 0.5, 1.0, or 2.0 millimeters of the skin. Optionally, the distance between the analyzer and the skin of the subject 170 is maintained with a vibration and/or shake reduction system, such as is used in a vibration reduction camera or lens. For clarity of presentation, the photons are depicted as entering the skin at a single point. A portion of the photons traverse, or more particularly traverse through, the skin to a detection zone. The detection zone is a region of the skin surface where the detector system 130 gathers the traversing or diffusely reflected photons. Various photons traversing or diffusely scattering through the skin encounter an epidermis 173 or epidermis layer, a dermis 174 or dermis layer, and subcutaneous fat 176 or a subcutaneous fat layer. As depicted in FIG. 2, the diffuse reflectance of the various photons through the skin detected by the detection system 130 follow a variety of optical paths through the tissue, such as shallow paths through the epidermis 173, deeper paths through the epidermis 173 and dermis 174, and still deeper paths through the epidermis 173, dermis 174, and subcutaneous fat 176. However, for a large number of photons, there exists a mean photon path for photons from entering the skin that are detected by the detection system 130. In the illustrations, optical pathlengths are illustrated as straight lines and/or curved lines for clarity of presentation; light travels in straight lines between multiple scattering events.

Pathlength

Herein, for clarity, without loss of generality, and without limitation, Beer's Law is used to described photon interaction with skin, though those skilled in the art understand deviation from Beer's Law result from sample scattering, index of refraction variation, inhomogeneity, turbidity, and/or absorbance out of a linear range of the analyzer 100.

Beer's Law, equation 1, states that:

AαbC  (eq. 1)

where A is absorbance, b is pathlength, and C is concentration. Typically, spectral absorbance is used to determine concentration. However, the absorbance is additionally related to pathlength. Hence, determination of the optical pathlength traveled by the photons is useful in reducing error in the determined concentration. Two methods, described infra, are optionally used to estimate pathlength: (1) spatial resolution of pathlength and (2) temporal resolution of pathlength.

Algorithm

The data and/or derived information from each of the spatial resolution method and temporal resolution method are each usable with the data processing system 140. Examples provide, infra, illustrate: (1) both cases of the spatial resolution method and (2) the temporal resolution method. However, for clarity of presentation and without limitation, the photons in most examples are depicted as radially traversing from a range of input zones to a detection zone. Similarly, photons are optionally delivered, simultaneously and/or as a function of time, from an input zone to a range of detection zones. Still further, photons are optionally directed to a series of input zones, as a function of time, and one or more detection zones are used to detect the photons directed to the series of input zones, simultaneously and/or as a function of time.

Spatial Resolution

The first method of spatial resolution contains two cases. Herein, in a first case photons are depicted traversing from a range of input points on the skin to a radially located detector to derive photon interrogated sample path and/or depth information. However, in a second case, similar systems optionally use a single input zone of the photons to the skin and a plurality of radially located detector zones to determine optical sample photons paths and/or depth information. Still further, a combination of the first two cases, such as multiple sources and multiple detectors, is optionally used to derive photon path information in the skin.

In the first system, Referring now to FIG. 3, the photon transit system 200 of FIG. 2 is illustrated where the photon transport system 110 irradiates the skin of the subject 170 over a wide range of radial distance from the detection zone, such as at least about 0.1, 0.2, 0.3, 0.4, or 0.5 millimeters from the detection zone to less than about 1.0, 1.2, 1.4, 1.6, or 1.8 millimeters from the detection zone. In this example, a mean photon path is provided as a function of radial distance from the illumination zone to the detection zone. Generally, over a range of about zero to less than about two millimeters from the detection zone, the mean optical path of the detected diffusely scattering photons increases in depth for photons in the near-infrared traveling through skin.

In the first case of the spatial resolution method, referring now to FIG. 4, the photon transit system 200 uses a vector or array of illumination sources 400, of the source system 110, in a spatially resolved pathlength determination system. For example, the illumination sources are an array of fiber optic cables. In this example, a set of seven fiber optics 401, 402, 403, 404, 405, 406, 407 are positioned, radially along the x,y plane of the subject 170 to provide a set of illuminations zones, relative to a detection fiber at a detection zone. As illustrated the third illumination fiber optic 403/detector 132 combination yields a mean photon path having a third depth of penetration, d₃, for a third fiber optic-to-detector radial distance, r₃; the fifth illumination fiber optic 405/detector 132 combination yields a mean photon path having a fifth depth of penetration, d₅, for a fifth fiber optic-to-detector radial distance, r₅; and the seventh illumination fiber optic 407/detector 132 combination yields a mean photon path having a seventh depth of penetration, d₇, for a seventh fiber optic-to-detector radial distance, r₇. Generally, for photons in the near-infrared region from 1100 to 2500 nanometers both a mean depth of penetration of the photons and a total optical pathlength increases with increasing fiber optic-to-detector distance, where the fiber optic-to-detector distance is less than about three millimeters.

In the second case of the spatial resolution method, referring now to FIG. 5, the photon transit system 200 uses a vector or array of detectors 500 in the detection system 130. For example, a single fiber optic source is used, which sends radially distributed light to an array of staring detectors or collection optics coupled to a set of detectors. In this example, a set of seven detectors 501, 502, 503, 504, 505, 506, 507 are positioned, radially along the x,y plane to provide a set of detection zones, relative to an illumination zone. As illustrated the source 112/second detector 502 combination yields a mean photon path having a second depth of penetration, d₂, for a second source-to-detector radial distance, r₂; the source 112/fourth detector 504 combination yields a mean photon path having a fourth depth of penetration, d₄, for a fourth source-to-detector radial distance, r₄; and the source 112/sixth detector 506 combination yields a mean photon path having a sixth depth of penetration, d₆, for a sixth source-to-detector radial distance, r₆. Again, generally for photons in the near-infrared region from 1100 to 2500 nanometers both the mean depth of penetration of the photons into skin and the total optical pathlength in skin increases with increasing fiber optic-to-detector distance, where the fiber optic-to-detector distance is less than about three millimeters. Hence, data collected with an analyzer configured with a multiple detector design generally corresponds to the first case of a multiple source design.

Referring again to FIGS. 4 and 5, the number of source zones, where light enters skin of the subject 170, from one or more source elements, is optionally 1, 2, 3, 4, 5, 10, 20, 50, 100 or more and the number of detection zones, where light exiting the skin of the subject 170 is detected by one or more detection elements and/or systems, is optionally 1, 2, 3, 4, 5, 10, 20, 50, 100, 500, 1000, 5000, 10,000, 50,000 or more.

Two-Dimensional Array Systems

Referring now to FIG. 6A, a m×n two-dimensional detector array 134 is illustrated, which is an example of the detector 132 in the detector system 130. Herein, the m×n two-dimensional detector array 134 is illustrated as a matrix of m columns by n rows, where m and n are each, not necessarily equal, positive integers, such as greater than 1, 2, 3, 4, 5, 10, 20, 50, 100. Optionally, the two-dimensional array detector 134 is of any geometric configuration, shape, or pattern. Preferably, but optionally, the two-dimensional detector array 134 is positioned perpendicular and axial to the optical light path at the detector. Optionally, the two-dimensional array detector 134 or a portion thereof is tilted off of the perpendicular axis, such as less than 1, 2, 3, 5, 10, or 15 degrees toward skin of the subject 170, which yields a range of applied pressures between the two-dimensional detector array and the skin when the two-dimensional detector array 134 or a layer thereon contacts the skin.

Referring now to FIG. 6B, the two-dimensional detector array 134 is further described. Optionally, one or more elements of the two-dimensional array is coated or coupled with an optical detector filter 620. In a first case, the optical detector filter 620 is uniform across the two-dimensional detector array 134. In a second case, the optical detector filter 620 comprises an array of filters, where individual elements, grids, or zones of the optical filter correspond to individual elements of two-dimensional array detector 134. For example, a group of at least 1, 2, 4, 9, 16, or 25 elements of the two-dimensional detector array 134 are optically coupled with a first optical filter and a group of at least 1, 2, 4, 9, 16, or elements of the two-dimensional detector array 134 are optically coupled to a second filter. Optionally, any number of filter types are used with a single detector array, such as 1, 2, 3, 4, 5, 10, 20 or more filter types. In a preferred embodiment, a first, second, third, fourth, and fifth filter type correspond with peak transmittance in ranges in the 1100 to 1450 nm range, 1450 to 1900 nm range, 1100 to 1900 nm range, 1900 to 2500 nm range, or 1100 to 2500 nm range, respectively, with lower transmittances, such as less than 50, 25, or 10 percent at higher and/or lower frequencies. In a third case, the optical filter 134 comprises a repeating pattern of transmittances and/or absorbances as a function of y, z-position.

Still referring to FIG. 6B, the two-dimensional detector array 134 is optionally coupled to a detector optic/micro-optic layer 630. In a first case, individual optical elements of the micro-optic layer 630 optionally:

-   -   alter a focal depth of incident light onto the two-dimensional         detector array 134;     -   alter an incident angle of incident light onto the         two-dimensional detector array 134; and/or     -   focus on an individual element of the two-dimensional detector         array 134.

In a second case, individual lines, circles, geometric shapes covering multiple detector elements, and/or regions of the micro-optic layer optionally:

-   -   alter a focal depth of incident light onto a line, circle,         geometric shape, and/or region of the two-dimensional detector         array 134;     -   alter an incident angle of incident light onto a line, circle,         geometric shape, and/or region of the two-dimensional detector         array 134; and/or     -   focus onto a line, circle, geometric shape, and/or region of a         group of elements of two-dimensional detector array 134.

Further the individual optical elements of the micro-optic layer 630 and/or the individual lines, circles, geometric shapes, or regions of the micro-optic layer 630 optionally are controlled by the system controller 180 to change any of the focal depth and/or the incident angle as a function of time within a single data collection period for a particular subject and/or between subjects.

Still referring to FIG. 6B, the optical detector filter 620 is:

-   -   optionally used with or without the detector optic/micro-optic         layer 630; and/or     -   optionally contacts, proximately contacts, or is separated by a         detector filter/detector gap distance from the two-dimensional         detector array 134.

Similarly, the detector optic/micro-optic layer 630 is:

-   -   optionally used with or without the optical detector filter 620;         and/or     -   optionally contacts, proximately contacts, or is separated by a         micro-optic/detector gap distance 632 from the two-dimensional         detector array 134.

Referring now to FIGS. 7A-E, for clarity of presentation, an incident optic/two-dimensional detector array system 700 is illustrated in multiple representative configurations, without loss of generality or limitation.

Referring now to FIG. 7A, a first example of the incident optic/two-dimensional array system 700 is illustrated with the photon transport system 120 used to deliver photons to the subject 170 proximate the two-dimensional detector array 134. In a first example, a portion of photons from the photon transport system diffusely scatter through skin of the subject 170 and after radial movement emerge from the skin of the subject 170 where they are detected by elements of the two-dimensional detector array 134. In a first example, photons are illustrated travelling along: (1) a mean first path, path₁, and are detected by a first detector element of the two-dimensional detector array 134 at a first, smaller, radial distance from a tissue illumination zone of the photon transport system and (2) a mean second path, path₂, and are detected by a second detector element of the two-dimensional detector array 134 at a second, longer, radial distance from a tissue illumination zone of the photon transport system relative to path₁. In this first example, optionally:

-   -   a first element of the optical detector filter 620 is preferably         a filter designed for a shorter mean tissue pathlength, such as         about 0 to 1.5 millimeters, such as a combination band optical         filter with a peak transmittance in a range of 2000 to 2500 nm;     -   a second element of the optical detector filter is preferably a         filter designed for a longer mean tissue pathlength, such as         about 5.0 to 10 millimeters, such as a second overtone optical         filter with a peak transmittance in a range of 1100 to 1450 nm;         and     -   a third element of the optical detector filter is preferably a         filter designed for an intermediate mean tissue pathlength, such         as about 1.5 to 5.0 millimeters, such as a first overtone         optical filter with a peak transmittance in a range of 1450 to         1900 nm.

In the first example,

-   -   a first element of the detector optic/micro-optic layer 630 is         optionally configured to preferably collect incident skin         interface light having an angle aimed back toward the photon         transport system, which yields a slightly longer shorter mean         tissue pathlength, such as about 0.2 to 1.7 millimeters compared         to an optic that is flat relative to the skin of the subject         170;     -   a first element of the detector optic/micro-optic layer 630 is         optionally configured to redirect collected incident skin         interface light back away from the photon transport system 120         as illustrated, such as onto a center of a detector or detector         array element closer to the illumination zone;     -   a second element of the detector optic/micro-optic layer 630 is         optionally configured to preferably collect incident skin         interface light having an angle aimed away from the incident         illumination zone of the skin, which yields a slightly shorter         mean tissue pathlength compared to an optic that is flat         relative to the skin of the subject 170;     -   a second element of the detector optic/micro-optic layer 630 is         optionally configured to redirect collected incident skin         interface light back toward the incident skin illumination zone,         such as onto a center of a detector or detector array element         further from the illumination zone;     -   a third element of the detector optic/micro-optic layer 630 is         optionally flat relative to a mean plane between the skin of the         subject 170 and the two-dimensional detector array 134.

As described, supra, the individual optical elements of the micro-optic layer 630 and/or the individual lines, circles, geometric shapes, or regions of the micro-optic layer 630 are optionally controlled by the system controller 180 to change any of a detector layer incidence acceptable angle, the focal depth, an incident angle, and/or an emittance angle or exit angle as a function of time within a single data collection period for a particular subject and/or between subjects.

Still referring to FIG. 7A, an optional micro-optic layer/detector array gap 632 is illustrated between the detector optic/micro-optic layer 630 and the two-dimensional detector array 134, such as a gap less than 0.2, 0.5, 1, 2, 5, or 10 millimeters. Further, an optional spacer gap 121 is illustrated between a final incident optic of the photon transport system 120 and any of the two-dimensional detector array 134, the optical detector filter 620, and the detector optic/micro-optic layer 630, such as a gap of less than about 0.1, 0.2, 0.3, 0.4, 0.5, 0.75, and millimeter.

Referring now to FIG. 7B, a second non-limiting example of the incident optic/two-dimensional array system 700 is illustrated with the photon transport system 120 used to deliver photons to the subject 170 proximate a first side of the two-dimensional detector array 134, where the array has n detector elements, where n is a positive integer greater than three. In this second example, ten radial distances to ten detector elements are illustrated. In this example, some radial distances are equal, such as a first radial distance to detector elements 1 and 5 and a second radial distance to detector elements 2 and 4. Generally, detector elements are optionally grouped or clustered into radial distances relative to an illumination zone of 1, 2, 3, or more incident light directing elements where each group or cluster is individually associated with an average mean optical probed tissue pathlength, subsequently used in pathlength resolution.

Still referring to FIG. 7B, optionally, different clusters of radial distances are treated optically differently, such as with a different optical detector filter 620. Representative and non-limiting examples include:

-   -   a combination band filter for filtering photons having mean         radial distances of 0 to 1 millimeter, the combination band         filter comprising:         -   a transmittance greater than seventy percent at 2150 nm,             2243, and/or 2350 nm, and/or         -   an average transmittance of greater than seventy percent             from 2100 to 2400 nm and an average transmittance of less             than twenty percent from 1100 to 1900 nm and/or from 2400 to             2600 nm;     -   a first overtone band filter for filtering photons having mean         radial distances of 0.3 to 1.5 millimeters, the first overtone         filter comprising:         -   a transmittance greater than seventy percent at 1550 nm,             1600, and/or 1700 nm, and/or         -   an average transmittance of greater than seventy percent             from 1500 to 1800 nm and an average transmittance of less             than twenty percent from 1100 to 1400 nm and/or from 2000 to             2600 nm;     -   a combination band/first overtone band filter for filtering         photons having mean radial distances of 0 to 1.5 millimeters,         the combination/first overtone filter comprising:         -   a transmittance greater than seventy percent at 1600 and             2100 nm, and/or         -   an average transmittance of greater than seventy percent             from 1500 to 2300 nm and an average transmittance of less             than twenty percent from 700 to 1400 nm and/or from 2500 to             2800 nm;     -   a second overtone band filter for filtering photons having mean         radial distances of 0.5 to 3.0 millimeters, the second overtone         filter comprising:         -   a transmittance greater than seventy percent at 1200 nm,             1600, and/or 1300 nm, and/or         -   an average transmittance of greater than seventy percent             from 1100 to 1400 nm and an average transmittance of less             than twenty percent from 700 to 1000 nm and/or from 1500 to             2000 nm;     -   a first overtone band/second overtone band filter for filtering         photons having mean radial distances of 0.5 to 3.0 millimeters,         the first overtone band/second overtone band filter comprising:         -   a transmittance greater than seventy percent at 1300 and             1600 nm, and/or         -   an average transmittance of greater than seventy percent             from 1200 to 1700 nm and an average transmittance of less             than twenty percent from 700 to 1000 nm and/or from 2500 to             3000 nm;     -   a sloping overtone bands filter for filtering photons having         mean radial distances of 0.5 to 3.0 millimeters, the sloping         overtone bands filter comprising:         -   a mean transmittance greater than ten percent at 1300 nm,             less than fifty percent at 1300 nm, and greater than seventy             percent at 1600 nm, and/or         -   an average transmittance between 1100 and 1300 nm in the             range of ten to fifty percent and an average transmittance             between 1500 and 1700 nm of greater than seventy percent             with optional out of band blocking from 700 to 1000 nm             and/or from 2500 to 3000 nm of greater than ninety percent;             and/or     -   a luminance filter for filtering photons having mean radial         distances of 0 to 5 millimeters, the luminance first comprising:         -   an optical spacing element designed to maintain focal             length;         -   a mean transmittance greater than seventy percent from 1100             to 1800 nm, and/or         -   a mean transmittance greater than seventy percent from 1100             to 2400 nm and an average transmittance of less than twenty             percent from 1100 to 1400 nm and/or from 2000 to 2600 nm.

Referring now to FIGS. 7B, 7C, and 7D, the photon transport system 120 is illustrated as delivering light to an edge, corner, and interior region of the two-dimensional detector array 134, respectively. Descriptions, herein, to the edge, corner, or interior illumination options optionally apply to the other cases.

Referring again to FIG. 7B, the photon transport system 120 is illustrated delivering photons using and/or through one or more optics to a point along an edge of the two-dimensional detector array 134. For clarity of presentation, in a first case, the photon transport system 120 is illustrated delivering photons to a center of an edge of the two-dimensional detector array 134; however, the photon transport system 120 optionally delivers photons to any point along the edge of the two-dimensional detector array 134 and/or at any distance from an edge or corner of the two-dimensional detector array.

Still referring to FIG. 7B, as illustrated the photon transport system delivers photons that are detected with an array of pathlengths and associated mean depths of penetration into the tissue of the subject 170, at each detector element. For example, the first detector element, 1, detects photons having a first pathlength for a first illumination point, herein denoted b_((pathlength, illuminator)). In the first case, using a simplifying assumption of tissue homogeneity for clarity of presentation, the mean probed pathlength is the same at the first and fifth detector elements. Similarly, the mean probed pathlength is similar and/or tightly grouped at the second and fourth detector element. In addition, groups of detector elements observe photons traversing similar or grouped pathlengths. For example, a first sub-group of the first, sixth, and seventh detector elements observe similar probed tissue pathlengths and depths of penetration. Similarly, a second sub-group of the fifth, ninth, and tenth detector elements observe similar probed tissue pathlengths and depths of penetration. In this case, the first sub-group and second sub-group are optionally placed into a single group as the first sub-group and second sub-group observe similar, exact if the tissue is homogenous, probed tissue pathlengths. Similarly, a first sub-group is optionally one, two, three, or more elements of a first column of detector elements and a second sub-group is optionally one, two, three, or more elements of a second column of the detector elements. Generally, the detector elements are optionally treated individually or in sub-groups, such as by distance from a mean sample illumination point, sub-groups of one or more rows of detector element, sub-groups of one or more columns of detector elements, and/or groups of sub-groups.

Still referring to FIG. 7B, any two-dimensional detector array 134 element, sub-group, column, row, region, and/or group is optionally individually coated or coupled to any filter, such as the filters described supra, and/or is optionally individually coupled with a focusing optic and/or a dynamic focusing optic.

Referring now to FIG. 7C, a second case of an illumination optic and/or a group of illumination optics of the photon transport system 120 used to illuminate an illumination zone relative to a corner of the two-dimensional detector array 134 is illustrated. As with the first side illumination case, individual elements, sub-groups, and/or groups of detector elements observe at differing radial distances from the illumination zone where the differing radial distances have corresponding average observed tissue pathlengths, depths of penetration, and/or sampled regions of skin of the subject 170. Here, three groups or detection zones are illustrated. The first group 710 is illustrated as detection elements 1, 2, 3, 4, 5, and 6, where the commonality is a short radial distance between the illumination zone and the detection zone, such as used for the combination band spectral region and/or for small mean depths of penetration of the photons into the tissue of the subject 170. The second group 720 is illustrated with long rising dashes, where the commonality is a medium radial distance between the illumination zone and the detection zone, such as used for the first overtone spectral region. The third group 730 is illustrated with short falling dashes, where the commonality is a long radial distance between the illumination zone and the detection zone, such as used for the second overtone spectral region. As described, supra, any detector element, group, sub-group, and/or group is optionally associated with an individual filter, an individual optic, and/or an individual dynamic optic.

Referring now to FIG. 7D, a third case of an illumination optic and/or a group of illumination optics of the photon transport system 120 used to illuminate an illumination zone relative to a section within the two-dimensional detector array 134 is illustrated. As with the first side illumination case and the second corner illumination case, individual elements, sub-groups, and/or groups of detector elements observe at differing radial distances from the illumination zone where the differing radial distances have corresponding average observed tissue pathlengths, depths of penetration, and/or sampled regions of skin of the subject 170. Here, two groups or detection zones are illustrated. The third group 740 is a first section, arc, quadrant, zone, ring, square, rectangle, and/or polygon of detection elements at a first range of distances from the illumination zone, illustrated here with detector elements intersecting with a long-dashed/square shape. The fourth group 750 is a second section, arc, quadrant, zone, ring, square, rectangle, and/or polygon of detection elements at a second range of distances from the illumination zone, shown here with detector elements intersecting with a short-dashed/square shape. The fourth group 740 and fifth group 750 are illustrative of n groups where n is a positive integer of 2, 3, 4, 5, 10 or more where individual groups differ by 1, 2, 3, 4 or more cross-sectional distances of a detector element. As described, supra, any detector element, group, sub-group, and/or group is optionally associated with an individual filter, an individual optic, and/or an individual dynamic optic.

Still referring to FIG. 7D, in one optional filter arrangement, optical filters are stacked. For example, a first optical filter is a first long pass or a short pass filter covering a wide range of first detector elements; a second optical filter is stacked relative to the first optical filter along the x-axis, which is the optical axis. The second optical filter is a second long pass, a second short pass, or a band pass filter covering a subset of the first detector elements. For example, the first optical filter is a long pass filter passing wavelengths longer than 1100 nm covering all of the fourth group 740 and fifth group 750, and the second optical filter is a long pass filter passing wavelength longer than 1450 nm covering all of the fifth group, which yields a first overtone filter for the fourth group 740 and a first and second overtone filter for the fifth group 750. Combinations of stacked filters for various groups include any of 2, 3, 4, or more filters described herein, such as the combination band filter, the first overtone band filter, the combination band/first overtone band filter, the second overtone band filter, the first overtone band/second overtone band filter, the sloping overtone bands filter, and the luminance filter described, supra, in the description of FIG. 7B. The inventor notes that cutting larger stackable filters reduces costs and more importantly light loss associated with placing individual filters over individual detector elements of the two-dimensional detector array 134.

Referring now to FIG. 7E, a fourth example of multiple illumination zones from the photon transport system 120 positioned about and within, not illustrated, the two-dimensional detector array 134 is illustrated. In this fourth example, a matrix of illuminators, herein represented by a single column for clarity of presentation, are denoted as illuminators a-z. At a given point in time, any set or subset of the matrix of illuminators are used to deliver photons to the tissue of the subject 170. For example, at a first point in time, illuminators a-b are used; at a second point in time illuminators a-d are used; at a third point time illuminators d-g are used, and so on. As illustrated, illuminators a-d are used and a detection element m,n is used. Generally, sets of illuminators are used as a function of time where the illuminators define the number of photons delivered and provide a first part of a illuminator-to-detector element distance and selected detector elements as the same function of time define the second part of the illuminator-to-detector distance.

Referring again to FIGS. 7B-E, notably, detector elements associated with a first sub-group or first group at a first point in time are optionally associated with an n^(th) sub-group or n^(th) group at a n^(th) point in time when the same and/or a different set of illuminators are used, where n is a positive integer of 2, 3, 4, 5, 10 or more.

Referring now to FIGS. 8A-D, a multiple luminance/multiple detector array system 800 is described. Generally, one and preferably two or more illumination zones are provided by the photon transport system within and/or about two or more detector arrays, such as two or more of the two-dimensional detector arrays 134. For clarity of presentation and without loss of generality, several examples are provided, infra, of the multiple luminance/multiple detector array system 800.

Referring now to FIG. 8A, a first example of the photon transport system 120 delivering light to the skin of the subject 170 at multiple illumination positions relative to two or more detector arrays, such as a first detector array 702 and a second detector array 704, is provided. In this first example, the photon transport system delivers light: (1) by the side 802, (2) removed from the side 804, (3) at the corner 806, and (4) around the corner 808 of a detector array, such as the second detector array 704. As illustrated, illumination zones are provided in a first column and in a second column relative to the side of the second detector. The first column 802 and the second column 804 of illuminators are illustrated proximately touching, with a first illuminator/detector gap 812, an edge of the second detector array 704 and with a second illuminator/detector gap 814 from the first detector array 702, where the first illuminator/detector gap 812 and the second illuminator/detector gap 814 are optionally different by greater than ten percent and are, respectively less than and greater than, about 1, ½, ¼, ⅛, 1/16, or 1/32 of a millimeter.

Referring now to FIG. 8B, a second example of the photon transport system 120 delivering light to the skin of the subject 170 at multiple illumination positions relative to two or more detector arrays, such as a first detector array 702 and a second detector array 704, is provided. In this second example, four detector arrays are illustrated about a single illumination array. In this second example, the first detector array is illustrated with a plurality of filters along rows of detector elements. For example, a first filter, illustrated as filter 1, is optionally a combination band filter; a second filter, illustrated as filter 2, is optionally a first overtone filter; a third filter, illustrated as filter 3, is optionally a first and second overtone filter; a fourth filter, illustrated as filter 4, is optionally a second overtone filter; and a fifth filter, illustrated as filter L, is optionally a luminance filter. The inventor notes that the filters are arranged in readily manufactured rows, provide a spread of radial distances within a row, and fall in an order of wavelength inversely correlating with mean pathlength as a function of radial distance from the illuminator. Referring now to a second detector array 704, a third detector array 706, and a fourth detector array 706 positioned about the illumination zone from the photon transport system 120, the inventor notes that the same five filters positioned in different configuration and/or orders as a function of radial distance from the illumination zone and/or as a function of rotation angle of the detector array yields a plurality of additional pathlengths. For brevity and clarity of presentation, only the first filter, filter 1, is addressed. In the first detector array 702, the first filter represents three distinct mean pathlengths from a mean illumination zone using the 1^(st) and 5^(th) detector elements, the 2^(nd) and 4^(th) detector elements, and the 3^(rd) detector element. Similarly, the second array filter 704 monitors two additional mean pathlengths from the mean illumination zone using the first filter and individual detector elements. The third detector array 706 could measure the same mean pathlengths as the second detector array 704; however, preferably the third detector array 706 measures still two more mean pathlengths using two pairs of detector elements with differing distances from the mean illumination zone. Similarly, the fourth detector array 708 optionally measures a number of yet still distinct mean pathlengths, such as by binning all six detector elements, or by binning rows of detector elements. Thus, at a first point in time, the four detector array 702, 704, 706, 708 optionally monitor at least eight mean pathlengths using only the first filter. At a second point in time, an additional distinct eight pathlengths are optionally monitored by illuminating a second pattern of the illustrated illumination points. The inventor notes that even illuminating all of the illumination points or only the first and second rings of illumination points, despite having the same mean point of illumination, will yield eight additional mean pathlengths in the tissue due to tissue inhomogeneity. Clearly, simultaneous use of the other four filters allows for simultaneous collections of spectra having at least forty pathlengths (8×5). Further, filter 1, is optionally different, in terms of a filter parameter such as a cut-on wavelength or a cut-off wavelength, for each detector array 702, 704, 706, 708 without complicating manufacturing, which yields still additional simultaneously probed optical tissue pathlengths. Generally, any number or detector elements, any number of detector arrays, any number of filters, and/or any geometry of filter layout are optionally used to obtain a desired number of simultaneously probed sample pathlengths. Optionally, signal from groups of common detector elements are binned to enhance a given signal-to-noise ratio.

Referring now to FIG. 8C, additional examples of two-dimensional detector arrays are provided. Referring now to the first detector array 702 and the second detector array 704, the second detector array 704 relative to the first detector array illustrates:

-   -   that two detector arrays optionally vary in length and/or width         by at least 5, 10, or 20 percent, which results in an ability to         miniaturize a sample probe head and/or to enhance collection         efficiency of delivered photons by increasing overall skin         surface coverage by the detectors; and     -   that the row and/or columns of detector elements optionally have         different single element sizes, which allows control over range         of pathlengths monitored with a given detector element.

Referring now to the third detector array 706, the two-dimensional detector array 134 optionally contains sensors and/or optics to measure a range of parameters, such as a local tissue temperature, T₁, a local tissue pressure, P₁, and/or a local illumination, I₁. Referring now to the fourth detector array 708, the two-dimensional detector array is designed to be read out in columns or sideways as rows, which allows each row to have a different detector element size. Increasing the detector element size as a function of radial distance away from an illuminator allows an enhanced/tuned signal-to-noise ratio as the detector aperture is larger as the number of photons exiting the skin with increased radial distances decreases. The larger aperture sizes of the detectors enhances signal-to-noise ratios as baseline noise remains constant and thermal noise increases at a smaller, less than linear, rate compared to the linear increase in signal with increased integration time. Referring now to the first through fourth detector arrays 702, 704, 706, 708, an optional range of illuminator/detector gaps are illustrated 121, 123, 125, 127 for the first through fourth detector arrays 702, 704, 706, 708, respectively.

Referring now to FIG. 8D, yet another example of a multiple two-dimensional detector array system is provided. In this example, a first detector array 702 is configured with zones of regularly shaped filters over multiple individual detector element sizes. For example, a first filter, such as a first overtone filter, covers two rows of detector elements, which aids in filter costs, alignment, masks, and/or installation. The first row of detector elements comprises smaller dimensions than the second row of detector elements, which enhances signal-to-noise ratios in each row as the time to fill detector wells in the first row of detector elements is less than the time to fill detector wells in the second row of detector elements due to the light transport/scattering properties in the 1450 to 1900 nm spectral region. The larger aperture of the second row detector elements gathers more light as a function of time compared to the first row detector elements as an area of a detector element in the second row is at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 times larger than an area of a detector element in the first row. Similarly, the third and fourth rows of detector elements are optionally associated with a second optic, such as the first overtone/second overtone band filter. The third row of detector elements are larger than the first row of detector elements due to fewer photons from an illumination zone exiting the skin at greater distances from the illumination zone and smaller than the second row of detector elements due to the enlarged spectral bandwidth of the first overtone/second overtone band filter. The fifth row of detector elements optionally uses a fifth filter, such as a second overtone filter. Generally, the area of detector elements is preferably manufactured to inversely match light density exiting the skin of the subject 170 in each optically filtered wavelength range. Here, the first detector array 702 in this example is designed to optionally readout in rows, which allows different rows to comprise different sizes of detector elements.

Referring still to FIG. 8D, a second detector array 704 is presented in a rotated configuration about the x-axis relative to the first detector array 702. The rotation of the second detector array 704 yields a continuum of pathlength ranges for a row of detectors. For example, in the first detector array 702, the first row of detectors monitor four average pathlengths of illuminated tissue due to C2 symmetry of the detector elements in the first row, where for example the inner two detector elements observe a single first mean pathlength and the outer two detector elements observe a single second mean pathlength. However, in stark contrast, the first row of detector elements in the second detector array 704 monitor eight different mean optical pathlengths of light delivered by the photon transport system 120. Similarly, each row of detector elements in the second detector array 704 observe, simultaneously, more mean pathlengths of photons from the photon transport system 120 compared to a corresponding row of detector elements in the first detector array 702 due to the rotation of the second detector array in the y,z-plane relative to a line from a center of the second array detector to a center of the illumination zone.

Referring again to FIGS. 7 and 8, any detector array is optionally tilted along the y- and/or z-axes to yield varying degrees of force applied to a sampled tissue sample as a function of detector position when directly contacting the tissue or indirectly contacting the tissue via a fronting detector layer during sampling. The varying pressure results in data comprising varying and/or controllable pressure for ease in subsequent data processing, such as via binning, grouping, correlations, and/or differential measures.

Still referring to FIGS. 7 and 8, any detector array is optionally differentially cooled along the y- and/or z-axes, such as with a Peltier cooler on one side of the detector array, to yield varying degrees of temperature as a function of detector position when directly contacting the tissue or indirectly contacting the tissue via a fronting detector layer during sampling. The varying temperature results in data comprising varying and/or controllable temperature for ease in subsequent data processing, such as via binning, grouping, correlations, and/or differential measures.

Temporal Resolution

The second method of temporal resolution is optionally performed in a number of manners. For clarity of presentation and without limitation, a temporal resolution example is provided where photons are timed using a gating system and the elapsed time is used to determine photon paths in tissue.

Referring now to FIGS. 9A-D, an example of a temporally resolved gating system 900 is illustrated. Generally, in the temporal gating system 900 the time of flight of a photon is used to determine the pathlength, b. Referring now to FIG. 9A, at an initial time, t₀, an interrogation pulse 910 of one or more photons is introduced to the sample, which herein is skin of the subject 170. The interrogation pulse 910 is also referred to as a pump pulse or as a flash of light. At one or more subsequent gated detection times 920, after passing through the sample the interrogation pulse 910 is detected. As illustrated, the gated detection times are at a first time 922, t₁; a second time 924, t₂; a third time 926, t₃; and at an n^(th) time 928, t_(n), where n is a positive number. Optionally, the gated detection times 920 overlap. For the near-infrared spectral region, the elapsed time used to detect the interrogation photons 910 is on the order of picoseconds, such as less than about 100, 10, or 1 picosecond. The physical pathlength, b, is determined using equation 2:

OPD=c/n(b)  (eq. 2)

where OPD is the optical path distance, c is the speed of light, n is the index of refraction of the sample, and b is the physical pathlength. Optionally, n is a mathematical representation of a series of indices of refraction of various constituents of skin and/or skin and surrounding tissue layers. More generally, observed pathlength is related to elapsed time between photon launch and photon detection where the pathlength of photons in the sample is related to elapsed time, optionally with one or more additional variables related to one or more refractive indices.

Referring now to FIG. 9B, illustrative paths of the photons for the first gated detection time 922 are provided. A first path, p_(1a); second path, p_(1b); and third path, p_(1c), of photons in the tissue are illustrated. In each case, the total pathlength, for a constant index of refraction, is the same for each path. However, the probability of each path also depends on the anisotropy of the tissue and the variable indices of refraction of traversed tissue voxels.

Referring now to FIG. 9C, illustrative paths of the photons for the second gated detection time 924 are provided. A first path, p_(2a); second path, p_(2b); and third path, p_(2c), of photons in the tissue are illustrated. Again, in each case the total pathlength for the second elapsed time, t₂, is the same for each path. Generally, if the delay to the second gated detection time 924 is twice as long as the first gated detection time 922, then the second pathlength, p₂, for the second gated detection time 924 is twice as long as the first pathlength, p₁, for the first gated detection time 922. Knowledge of anisotropy is optionally used to decrease the probability spread of paths observed in the second set of pathlengths, p_(2a), p_(2a), p_(2c). Similarly a-priori knowledge of approximate physiological thickness of varying tissue layers, such as an epidermal thickness of a patient, an average epidermal thickness of a population, a dermal thickness of a patient, and/or an average dermal thickness of a population is optionally used to reduce error in an estimation of pathlength, a product of pathlength and a molar absorptivity, and/or a glucose concentration by limiting bounds of probability of a photon traversing different pathways through the skin layers and still returning to the detection element with the elapsed time. Similarly, knowledge of an index of refraction of one or more sample constituents and/or a mathematical representation of probable indices of refraction is also optionally used to reduce error in estimation of a pathlength, molar absorptivity, and/or an analyte property concentration estimation. Still further, knowledge of an incident point or region of light entering she skin of the subject relative to a detection zone is optionally used to further determine probability of a photon traversing dermal or subcutaneous fat layers along with bounding errors of pathlength in each layer.

Referring now to FIG. 9D, mean pathlengths and trajectories are illustrated for three elapsed times, t₁, t₂, t₃. As with the spatially resolved method, generally, for photons in the near-infrared region from 1100 to 2500 nanometers, both a mean depth of penetration of the photons, d_(n); the total radial distance traveled, r_(m); and the total optical pathlength increases with increasing time, where the fiber optic-to-detector distance is less than about three millimeters. Preferably, elapsed times between a pulse of incident photon delivery and time gated detection are in a range between 100 nanoseconds and 100 picoseconds, such as about 1, 5, 10, and 50 picoseconds.

Spatial and Temporal Resolution

Hence, both the spatial resolution method and temporal resolution method yield information on pathlength, b, which is optionally used by the data processing system 140 to reduce error in the determined concentration, C.

Analyzer and Subject Variation

As described, supra, Beer's Law states that absorbance, A, is proportional to pathlength, b, times concentration, C. More precisely, Beer's Law includes a molar absorbance, ε, term, as shown in equation 3:

A=εbC  (eq. 3)

Typically, spectroscopists consider the molar absorbance as a constant due to the difficulties in determination of the molar absorbance for a complex sample, such as skin of the subject 170. However, information related to the combined molar absorbance and pathlength product for skin tissue of individuals is optionally determined using one or both of the spatially resolved method and time resolved method, described supra. In the field of noninvasive glucose concentration determination, the product of molar absorbance and pathlength relates at least to the dermal thickness of the particular individual or subject 170 being analyzed. Examples of spatially resolved analyzer methods used to provide information on the molar absorbance and/or pathlength usable in reduction of analyte property estimation or determination are provided infra.

Spatially Resolved Analyzer

Herein, an analyzer 100 using fiber optics is used to describe obtaining spatially resolved information, such as pathlength and/or molar absorbance, of skin of an individual, which is subsequently used by the data processing system 140. The use of fiber optics in the examples is used without limitation, without loss of generality, and for clarity of presentation. More generally, photons are delivered in quantities of one or more through free space, through optics, and/or off of reflectors to the skin of the subject 170 as a function of distance from a detection zone.

Referring again to FIG. 1 and referring now to FIG. 10A, an example of a fiber optic interface system 1000 of the analyzer 100 to the subject 170 is provided, which is an example of the sample interface system 150. Light from the source system 110 of the analyzer 100 is coupled into a fiber optic illumination bundle 1014 of a fiber optic bundle 1010. The fiber optic illumination bundle 1014 guides light to a sample site 178 of the subject 170. The sample site 178 has a surface area and a sample volume. In a first case, a sample interface tip 1016 of the fiber optic bundle 1010 contacts the subject 170 at the sample site 178. In a second case, the sample interface tip 1016 of the fiber optic bundle 1010 proximately contacts the subject 170 at the sample site 178, but leaves a sample interface gap 1020 between the sample interface tip 1016 of the fiber optic bundle 1010 and the subject 170. In one instance, the sample interface gap 1020 is filled with a contact fluid and/or an optical contact fluid. In a second instance, the sample interface gap 1020 is filled with air, such as atmospheric air. Light transported by the fiber optic bundle 1010 to the subject 170 interacts with tissue of the subject 170 at the sample site 178. A portion of the light interacting with the sample site is collected with one or more fiber optic collection fibers 1018, which is optionally and preferably integrated into the fiber optic bundle 1010. As illustrated, a single collection fiber 718 is used. The collection fiber 1018 transports collected light to the detector 132 of the detection system 130.

Referring now to FIG. 10B, a first example of a sample side light collection end 1016 of the fiber optic bundle 1010 is illustrated. In this example, the single collection fiber 1018 is circumferentially surrounded by an optional spacer 1030, where the spacer has an average radial width of less than about 200, 150, 100, 50, or 25 micrometers. The optional spacer 1030 is circumferentially surrounded by a set of fiber optic elements 1013. As illustrated, the set of fiber optic elements 1013 are arranged into a set of radial dispersed fiber optic rings, such as a first ring 1041, a second ring 1042, a third ring 1043, a fourth ring 1044, and an n^(th) ring 1045, where n comprises a positive integer of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10. Optionally, the fiber optic elements 1013 are in any configuration, such as in a close-packed configuration about the collection fiber 1018 or in an about close-packed configuration about the collection fiber 1018. The distance of each individual fiber optic of the set of fiber optic elements 1013, or light collection element, from the center of the collection fiber 1018 is preferably known.

Referring now to FIG. 10C, a second example of the sample side light collection end 1016 of the fiber optic bundle 1010 is provided. In this example, the centrally positioned collection fiber 1018 is circumferentially surrounded by a set of spacer fibers 1050. The spacer fibers combine to cover a radial distance from the outside of the collection fiber of less than about 300, 200, 150, 100, 75, 60, 50, or 40 micrometers. The spacer fibers 1050 are circumferentially surrounded by the radially dispersed fiber optic rings, such as the first ring 1041, the second ring 1042, the third ring 1043, the fourth ring 1044, and the n^(th) ring 1045. Optionally, fiber diameters of the spacer fibers 1050 are at least ten, twenty, or thirty percent larger or smaller than fiber diameters of the set of fiber optic elements 1013. Further, optionally the fiber optic elements 1013 are arranged in any spatial configuration radially outward from the spacer fibers 1050. More generally, the set of fiber optic elements 1013 and/or spacer fibers 1050 optionally contain two, three, four, or more fiber optic diameters, such as any of about 40, 50, 60, 80, 100, 150, 200, or more micrometers. Optionally, smaller diameter fiber optics, or light collection optics, are positioned closer to any detection fiber and progressively larger diameter fiber optics are positioned, relative to the smaller diameter fiber optics, further from the detection fiber.

Radial Distribution System

Referring now to FIG. 11A, FIG. 11B and FIG. 12, and FIGS. 13 A-D a system for spatial illumination 1100 of the sample site 178 of the subject 170 is provided. The spatial illumination system 1100 is used to control distances between illumination zones and detection zones as a function of time. In a first case, light is distributed radially relative to a detection zone using a fiber optic bundle. In a second case, light is distributed radially relative to a detection zone using a reflective optic system and/or a lens system. Generally, the first case and second case are non-limiting examples of radial distribution of light about one or more detection zones as a function of time.

Radial Position Using Fiber Optics

Referring now to FIG. 11A, a third example of the sample side light collection end 1016 of the fiber optic bundle 1010 is provided. In this example, the collection fiber 1018 or collection optic is circumferentially surrounded by the set of fiber optic elements 1013 or irradiation points on the skin of the subject 170. For clarity of presentation and without loss of generality, the fiber optic elements 1013 are depicted in a set of rings radially distributed from the collection fiber 1018. However, it is understood that the set of fiber optics 1013 are optionally close packed, arranged in a random configuration, or arranged according to any criterion. Notably, the distance of each fiber optic element of the set of fiber optic elements 1013 from the collection fiber 1018 is optionally determined using standard measurement techniques through use of an algorithm and/or through use of a dynamically adjustable optic used to deliver light to the sample, such as through air. Hence, the radial distribution approach, described infra, is optionally used for individual fiber optic elements and/or groups of fiber optic elements arranged in any configuration. More generally, the radial distribution approach, described infra, is optionally used for any set of illumination zone/detection zone distances using any form of illuminator and any form of detection system, such as through use of the spatially resolved system and/or the time resolved system.

Referring now to FIG. 11B, an example of a light input end 1012 of the fiber optic bundle 1010 is provided. In this example, individual fibers of the set of fiber optics 1013 having the same or closely spaced radial distances from the collection fiber 1018 are grouped into a set of fiber optic bundles or a set of fiber optic bundlets 1110. As illustrated, the seven fibers in the first ring circumferentially surrounding the collection fiber 1018 are grouped into a first bundlet 1111. Similarly, the sixteen fibers in the second ring circumferentially surrounding the collection fiber 1018 are grouped into a second bundlet 1112. Similarly, the fibers from the third, fourth, fifth, and sixth rings about the collection fiber 1018 at the sample side illumination end 1016 of the fiber bundle 1010 are grouped into a third bundlet 1113, a fourth bundlet 1114, a fifth bundlet 1115, and a sixth bundlet 1116, respectively. For clarity of presentation, the individual fibers are not illustrated in the second, third, fourth, fifth, and sixth bundlets 1112, 1113, 1114, 1115, 1116. Individual bundles and/or individual fibers of the set of fiber optic bundlets 1110 are optionally selectively illuminated using a mask 1120, described infra.

Referring now to FIG. 12 and FIG. 10A, a mask wheel 1130 is illustrated. Generally, the mask wheel 1130 rotates, such as through use of a wheel motor 1120. As a function of mask wheel rotation position, holes or apertures through the mask wheel 1130 selectively pass light from the source system 110 to the fiber optic input end 1012 of the fiber optic bundle 1010. In practice, the apertures through the mask wheel are precisely located to align with (1) individual fiber optic elements of the set of fiber optics at the input end 1012 of the fiber optic bundle or (2) individual bundlets of the set of fiber optic bundlets 1110. Optionally an encoder or marker section 1140 of the mask wheel 1130 is used for tracking, determining, and/or validating wheel position in use.

Still referring to FIG. 12, an example of use of the mask wheel 1130 to selectively illuminate individual bundlets of the set of fiber optic bundlets 1110 is provided. Herein, for clarity of presentation the individual bundlets are each presented as uniform size, are exaggerated in size, and are repositioned on the wheel. For example, as illustrated a first mask position, p₁, 1121 is illustrated at about the seven o'clock position. The first mask position 1121 figuratively illustrates an aperture passing light from the source system 110 to the first bundlet 1111 while blocking light to the second through sixth bundlets 1112-1116. At a second point in time, the mask wheel 1130 is rotated such that a second mask position, p₂, 1122 is aligned with the input end 1012 of the fiber optic bundle 1010. As illustrated, at the second point in time, the mask wheel 1130 passes light from the illumination system 110 to the second bundlet 1112, while blocking light to the first bundlet 1111 and blocking light to the third through six bundlets 1113-1116. Similarly, at a third point in time the mask wheel uses a third mask position, p₃, 1123 to selectively pass light into only the fifth bundlet 1115. Similarly, at a fourth point in time the mask wheel uses a fourth mask position, p₄, 1124 to selectively pass light into only the sixth bundlet 1116.

Still referring to FIG. 12, thus far the immediately prior example has only shown individual illuminated bundlets as a function of time. However, combinations of bundlets are optionally illuminated as a function of time. In this continuing example, at a fifth point in time, the mask wheel 1130 is rotated such that a fifth mask position, p₅, 1125 is aligned with the input end 1012 of the fiber optic bundle 1010. As illustrated, at the fifth point in time, the mask wheel 1130 passes light from the illumination system 110 to all of (1) the second bundlet 1112, (2) the third bundlet 1113, and (3) the fourth bundlet 1114, while blocking light to all of (1) the first bundlet 1111, (2) the fifth bundlet 1115, and (3) the sixth bundlet 1116. Similarly, at a sixth point in time a sixth mask position, p₆, 1126 of the mask wheel 1130 passes light to the second through fifth bundlets 1112-1115 while blocking light to both the first bundlet 1111 and sixth bundlet 1116.

In practice, the mask wheel 1130 contains an integral number of n positions, where the n positions selectively illuminate and/or block any combination of: (1) the individual fibers of the set of fiber optics 1013 and/or (2) bundlets 1110 of the set of fiber optic optics 1013. Further, the filter wheel is optionally of any shape and uses any number of motors to position mask position openings relative to selected fiber optics. Still further, in practice the filter wheel is optionally any electro-mechanical and/or electro-optical system used to selectively illuminate the individual fibers of the set of fiber optics 1013. Yet still further, in practice the filter wheel is optionally any illumination system that selectively passes light to any illumination optic or illumination zone, where various illumination zones illuminate various regions of the subject 170 as a function of time. The various illumination zones alter the effectively probed sample site 178 or region of the subject 170.

Radial Position Using a Mirror and/or Lens System

Referring now to FIG. 13, a dynamically positioned optic system 1000 for directing incident light to a radially changing position about a collection zone is provided.

Referring now to FIG. 13A, a mirror 1310 is illustrative of any mirror, lens, mirror system, and/or lens system used to dynamically and positionally direct incident light to one or more illumination zones of the subject 170 relative to one or more detection zones and/or volumes monitored by the photon transport system 120 and/or the detector system 130.

Still more generally, the data processing system 140 and/or the system controller 180 optionally control one or more optics, figuratively illustrated as the mirror 1010, to dynamically control incident light 711 on the subject 170 relative to a detection zone on the subject 170 that combine to form the sample site 178 through control of one or more of:

-   -   x-axis position of the incident light on the subject 170;     -   y-axis position of the incident light on the subject 170;     -   solid angle of the incident light on a single fiber of the fiber         bundle 710;     -   solid angle of incident light on a set of fibers of the fiber         bundle 710;     -   a cross-sectional diameter or width of the incident light;     -   an incident angle of the incident light on the subject 170         relative to an axis perpendicular to skin of the subject 170         where the incident light interfaces to the subject 170;     -   focusing of the incident light; and/or     -   depth of focus of the incident light on the subject 170.

Several examples are provided, infra, to further illustrate the use of the system controller 180 to control shape, position, and/or angle of the incident light 711 reaching a fiber optic bundle, skin of the subject 170, and/or an element of the photon transport system 120.

Referring again to FIG. 13A, an example is provided of light directed by the photon transport system 120 from the source system 110 to the subject directly, through one or more fiber optic of the fiber optic bundle 710, and/or through the photon transport system 120. However, orientation of the mirror 1310 is varied as a function of time relative to an incident set of photons pathway. For example, the mirror 1310 is translated along the x-axis of the mean optical path, is rotated about the y-axis of the mean optical path, and/or is rotated about the z-axis of the mean optical path of the analyzer 100. For example, a first mirror movement element 1322, such as a first spring or piezoelectric device, and a second mirror movement element 1324, such as a second spring, combine to rotate the mirror about the y-axis as illustrated. Similarly, a third mirror movement element 1326, such as a third spring, and a fourth mirror movement element 1328, such as a fourth spring, combine to rotate the mirror about the z-axis as illustrated in the second time position, t₂, relative to a first time position, t₁.

Referring now to FIG. 13B, an example of the dynamically positioned optic system 1300 directing the incident light 1011 to a plurality of positions as a function of time is provided. As illustrated, the mirror 1310 directs light to the light input end 1012 of the fiber bundle 1010. Particularly, the incident light 1011 is directed at a first time, t₁, to a first fiber optic 1051 and the incident light 1011 is directed at a second time, t₂, to a second fiber optic 1052 of a set of fiber optics 1050. However, more generally, the dynamically positioned optic system 1300 directs the incident light using the mirror 1300 to any y-, z-axis position along the x-axis of the incident light as a function of time, such as to any optic and/or to a controlled position of skin of the subject 170.

Referring now to FIG. 13C, an example of the dynamically positioned optic system 1000 directing the incident light to a plurality of positions with a controllable and varying as a function of time solid angle is provided. Optionally, the solid angle is fixed as a function of time and the position of the incident light 1011 onto the light input end 1012 of the fiber bundle 1010 is varied as a function of time. As illustrated, the mirror 1310 directs light to the light input end 1012 of the fiber bundle 1010 where the fiber bundle 1010 includes one or more bundlets, such as the set of fiber optic bundlets 1110. In this example, the incident light is directed at a first time, t₁, with a first solid angle to a first fiber optic bunch or group, such as the first bundlet 1111, described supra, and at a second time, t₂, with a second solid angle to a second fiber optic bunch, such as the second bundlet 1112, described supra. However, more generally, the dynamically positioned optic system 1300 directs the incident light to any y-, z-axis position along the x-axis of the incident light as a function of time at any solid angle or with any focusing angle, such as to any optic, any group of optics, and/or to a controlled position and/or size of skin of the subject 170 relative to a detection zone.

Referring now to FIG. 13D, an example is provided of the dynamically positioned optic system 1300 directing the incident light to a plurality of positions with a varying incident angle onto skin of the subject 170. As illustrated, the mirror 1310 directs light directly to the subject 170 without an optic touching the subject 170 or without touching a coupling fluid on the subject 170. However, alternatively the light is redirected after the mirror 1310, such as with a grins lens on a fiber optic element of the fiber optic bundle 1010. In this example, the incident light is directed at a first time, t₁, with a first incident angle, θ₁, and at a second time, t₂, with a second incident angle, θ₂. However, more generally, the dynamically positioned optic system 1300 directs the incident light to any y-, z-axis position along the x-axis of the incident light as a function of time at any solid angle, with any focusing depth, and/or an any incident angle, such as to any optic and/or to a controlled position and/or size of skin of the subject 170 relative to a detection zone. In this example, the detection zone is a volume of the subject monitored by the photon transport system 120 and/or a lens or mirror of the photon transport system 120 as interacting with the detector system 130 and a detector therein.

Adaptive Subject Measurement

Delivery of the incident light 1011 to the subject 170 is optionally varied in time in terms of position, radial position relative to a point of the skin of the subject 170, solid angle, incident angle, depth of focus, energy, and/or intensity. Herein, without limitation a spatial illumination system is used to illustrate the controlled and variable use of incident light.

Referring now to FIG. 14A and FIG. 14B, examples of use of a spatial illumination system 1400 are illustrated for a first subject 171 and a second subject 172. However, while the examples provided in this section use a fiber optic bundle to illustrate radially controlled irradiation of the sample, the examples are also illustrative of use of the dynamically positioned optic system 1300 for directing incident light to a radially changing position about a collection zone. Still more generally the photon transport system 120 in FIGS. 14A and 14B is used in any spatially resolved system and/or in any time resolved system to deliver photons as a function of radial distance to a detector or to a detection zone.

Referring now to FIG. 14A and FIG. 12, an example of application of the spatial illumination system 1100 to the first subject 171 is provided. At a first point in time, the first position, p₁, 1121 of the filter wheel 1130 is aligned with the light input end 1012 of the fiber bundle 1010, which results in the light from the first bundlet 1111, which corresponds to the first ring 1041, irradiating the sample site 178 at a first radial distance, r₁, and a first depth, d₁, which as illustrated in FIG. 11A has a mean optical path through the epidermis. Similarly, at a second point in time, the filter wheel 1130 at the second position 1122 passes light to the second bundlet 1112, which corresponds to the second ring, irradiating the sample site 178 at a second increased distance and a second increased depth, which as illustrated in FIG. 14A has a mean optical path through the epidermis and dermis. The dynamically positioned optic system 1300 is optionally used to direct light as a function of time to the first position 1121 and subsequently to the second position 1122. Similarly, results of interrogation of the subject 170 with light passed through the six illustrative fiber illumination rings in FIG. 11A is provided in Table 1. The results of Table 1 demonstrate that for the first individual, the prime illumination rings for a blood analyte concentration determination are rings two through four as the first ring, sampling the epidermis, does not sample the blood filled dermis layer; rings two through four probe the blood filled dermis layer; and rings five and six penetrate through the dermis into the subcutaneous fat where photons are lost and the resultant signal-to-noise ratio for the blood analyte decreases.

TABLE 1 Subject 1 Illumination Ring Deepest Tissue Layer Probed 1 Epidermis 2 Dermis 3 Dermis 4 Dermis 5 Subcutaneous Fat 6 Subcutaneous Fat

Referring now to FIG. 14B and FIG. 11A, an example of application of the spatial illumination system 1100 to the second subject 172 is provided. Again, the dynamically positioned optic system 1300 is optionally used to deliver light to the spatial illumination system 1100. Results of interrogation of the subject 170 with light passed through the six illustrative fiber illumination rings in FIG. 8A is provided in Table 2. For the second subject, it is noted that interrogation of the sample with the fifth radial fiber ring, f₅, results in a mean optical path through the epidermis and dermis, but not through the subcutaneous fat. In stark contrast, the mean optical path using the fifth radial fiber ring, f₅, for the second subject 172 has a deepest penetration depth into the dermis 174. Hence, the fifth radial fiber ring, f₅, yields photons probing the subcutaneous fat 176 for the first subject 171 and yields photons probing the dermis 174 of the second subject 172. Hence, for a water soluble analyte and/or a blood borne analyte, such as glucose, the analyzer 100 is more optimally configured to not use both the fifth fiber ring, f₅, and the sixth fiber ring, f₆, for the first subject 171. However, analyzer 100 is more optimally configured to not use only the sixth fiber ring, f₆, for the second subject 172, as described infra.

TABLE 2 Subject 2 Illumination Ring Deepest Tissue Layer Probed 1 Epidermis 2 Dermis 3 Dermis 4 Dermis 5 Dermis 6 Subcutaneous Fat

In yet another example, light is delivered with known radial distance to the detection zone, such as with optics of the analyzer, without use of a fiber optic bundle and/or without the use of a filter wheel. Just as the illumination ring determines the deepest tissue layer probed, control of the irradiation zone/detection zone distance determines the deepest tissue layer probed.

Incident Light Control

Referring again to FIGS. 13A-D, the dynamically positioned optic system 1300 is optionally used as a function of time to control one or more of:

-   -   delivery of the incident light 1011 to a single selected fiber         optic of the fiber optic bundle 1010;     -   delivery of the incident light 1011 to a selected bundlet of the         set of fiber optic bundlets 1110, such as to the first bundlet         1111 at a first point in time and to the second bundlet 1112 at         a second point in time;     -   variation of solid angle of the incident light 1011 to an optic         and/or to the subject 170;     -   variation of radial position of delivery of the incident light         1011 relative to a fixed location, such as a center of an optic,         a target point on skin of the subject 170, or a center of the         sample site 178;     -   incident angle of the incident light 1011 relative to a plane         tangential to the skin of the subject 170 and/or an axis normal         to the skin of the subject 170 at the sample site 178;     -   apparent focus depth of the incident light 1011 into the skin of         the subject 170;     -   energy; and     -   intensity, such as number of photon per second varying from one         point in time to another by greater than 1, 10, 50, 100, 500,         1000, or 5000 percent.

Time Resolved Spectroscopy

In still yet another example, referring again to time resolved spectroscopy, instead of delivering light through the filter wheel to force radial distance, photons are optionally delivered to the skin and the time resolved gating system is used to determine probably photon penetration depth. For example, Table 3 shows that at greater elapsed time to the n^(th) gated detection period, the probability of the deepest penetration depth reaching deeper tissue layers increases.

TABLE 3 Time Resolved Spectroscopy Elapsed Time (picoseconds) Deepest Tissue Layer Probed 1 Epidermis 10 Dermis 50 Dermis 100 Subcutaneous Fat

Data Processing

Referring now to FIG. 15, the data processing system 140 is further described. The data processing system 140 optionally uses a step of post-processing 1520 to process a set of collected data 1510. The post-processing step 1120 optionally operates on data collected as a function of any of: radial distance of the incident light 1011 to a reference point, such as a detector; solid angle of the incident light 1011 relative to the subject 170; angle of the incident light 1011 relative to skin of the subject 170; and/or depth of focus of the incident light 1011 relative to a surface of the skin of the subject 170.

Two-Phase Measurement(s)

Referring now to FIG. 16, in another embodiment, the analyzer 100 is used in two phase system 1600: (1) a sample mapping phase 1610, such as a subject or group mapping phase and (2) a subject specific data collection phase 1630. In one example, in the first mapping phase 1610, skin of the subject 170 is analyzed with the analyzer 100 using a first optical configuration. Subsequently, the mapping phase spectra are analyzed 1620. In the second subject specific data collection phase 1630, the analyzer 100 is setup in a second optical configuration based upon data collected in the sample mapping phase 1610. The second optical configuration is preferably configured to enhance performance of the analyzer 100 in terms of accuracy and/or precision of estimation and/or determination of an analyte property, such as a noninvasive glucose concentration. Examples provided, infra, use a single subject 170. However, more generally the sample mapping phase 1610 is optionally used to classify the subject into a group or cluster and the analyzer 100 is subsequently setup in a second optical configuration for the group or cluster, which represents a subset of the human population, such as by gender, age, skin thickness, water absorbance, fat absorbance, protein absorbance, epidermal thickness, dermal thickness, depth of a subcutaneous fat layer, and/or a model fit parameter. For clarity of presentation, several examples are provided infra describing use of a sample mapping phase 1610 and a subsequent subject specific data collection phase 1630.

In a first example, referring again to FIG. 14A and FIG. 14B, a first optional two-phase measurement approach is herein described. Optionally, during the first sample mapping phase 1610, the photon transport system 120 provides interrogation photons to a particular test subject at controlled, but varying, radial distances from the detection system 130. One or more spectral markers, or an algorithmic/mathematical representation thereof, are used to determine the radial illumination distances best used for the particular test subject. An output of the first phase is the data processing system 140 selecting how to illuminate/irradiate the subject 170. Subsequently, during the second subject specific data collection phase 130, the system controller 180 controls the photon transport system 120 to deliver photons over selected conditions and/or optical configuration to the subject 170.

In a second example, a first spectral marker is optionally related to the absorbance of the subcutaneous fat 176 for the first subject 171. During the first sample mapping phase 1610, the fifth and sixth radial positions of the fiber probe illustrated in FIG. 11A, yield collected signals for the first subject 171 that contain larger than average fat absorbance features, which indicates that the fifth and sixth fiber rings of the example fiber bundle should not be used in the subsequent second data collection phase, which more generally establishes an outer radial distance for subsequent illumination. Still in the first sample mapping phase 130, probing the tissue of the subject with photons from the fourth fiber ring yields a reduced signal for the first spectral marker and/or a larger relative signal for a second spectral marker related to the dermis 174, such as a protein absorbance band or an algorithmic/mathematical representation thereof. Hence, the data processing system 140 yields a result that the fifth and sixth radial fiber optic rings or distance of the fiber bundle 170 should not be used in the second subject specific data collection phase 1630 and that the fourth radial fiber optic ring or distance should be used in the second subject specific data collection phase 1630. Subsequently, in the second subject specific data collection phase 1630, data collection for analyte determination ensues using the first through fourth radial positions of the fiber bundle, which yields a larger signal-to-noise ratio for dermis constituents, such as glucose, compared to the use of all six radial positions of the fiber bundle.

In a third example, the first sample mapping phase 1610 of the previous example is repeated for the second subject 172. The first sample mapping phase 1610 indicates that for the second subject, the sixth radial illumination ring of the fiber bundle illustrated in FIG. 11A should not be used, but that the fourth and fifth radial illumination ring should be used.

In a fourth example, the first mapping phase 1610 determines positions on the skin where papillary dermis ridges are closest to the skin surface and positions on the skin where the papillary dermis valleys are furthest from the skin surface. In the subsequent subject specific data collection phase 1630, the incident light is optionally targeted at the papillary dermis valleys, such as greater than 50, 60, or 70 percent of the incident light is targeted at the papillary dermis valley and less than 30, 40, or 50 percent of the incident light is targeted at the papillary dermis ridge. The increased percentage of the incident light striking the papillary dermis valley increases the number of photons sampling the underlying dermis layer, where blood borne analytes reside, which increases the signal-to-noise ratio of collected data and lowers resultant errors in blood borne analyte property determination.

Generally, a particular subject is optionally probed in a sample mapping phase 1610 and results from the sample mapping phase 1610 are optionally used to configure analyzer parameters in a subsequent subject specific data collection phase 1630. While for clarity of presentation, and without loss of generality, radial distance was varied in the provided examples, any optical parameter of the analyzer is optionally varied in the sample mapping phase 1610, such as sample probe position, incident light solid angle, incident light angle, focal length of an optic, position of an optic, energy of incident light, and/or intensity of incident light. Optionally, the sample mapping phase 1610 and sample specific data collection phase 1630 occur within thirty seconds of each other. Optionally, the subject 170 does not move away from the sample interface 150 between the sample mapping phase 1610 and the subject specific data collection phase 130. Further, generally each of the spatial and temporal methods yield information on pathlength, b, and/or a product of the molar absorptivity and pathlength, which is not achieved using a standard spectrometer.

In yet another embodiment, the sample interface tip 1016 of the fiber optic bundle 1010 includes optics that change the mean incident light angle of individual fibers of the fiber optic bundle 1016 as they first hit the subject 170. For example, a first optic at the end of a fiber in the first ring 1041 aims light away from the collection fiber optic 1018; a second optic at the end of a fiber in the second ring 1042 aims light nominally straight into the sample; and a third optic at the end of a fiber in the third ring 1042 aims light toward the collection fiber 1018. Generally, the mean direction of the incident light varies by greater than 5, 10, 15, 20, or 25 degrees.

Data Processing System

The data processing system 140 is further described herein. Generally, the data processing system uses an instrument configuration analysis system 1640 to determine an optical configuration of the analyzer 100 and/or a software configuration of the analyzer 100 while the sample property analysis system 1650 is used to determine a chemical, a physical, and/or a medical property, such as an analyte concentration, measured or represented by collected spectra. Further, the data processing system 140 optionally uses a preprocessing step and a processing step to determine an instrument configuration and/or to determine an analyte property.

In one embodiment, the data processing system 140 uses a preprocessing step to achieve any of: lower noise and/or higher signal. Representative and non-limiting forms of preprocessing include any of: use of a digital filter, use of a convolution function, use of a derivative, use of a smoothing function, use of a resampling algorithm, and/or a form of assigning one or more spectra to a cluster of a whole. The data processing system subsequently uses any multivariate technique, such as a form of principal components regression, a form of partial least squares, and/or a form of a neural network to further process the pre-processed data.

In another embodiment, the data processing system 140 and/or the sample property analysis system 1650 operates on spectra collected by the analyzer 100, such as in the subject specific data collection phase 1630, using a first step of defining finite width channels and a second step of feature extraction, which are each further described, infra.

Finite Width Channels

In one example, the sample property analysis system 1650 defines a plurality of finite width channels, where the channels relate to changes in an optical parameter, software setting of the analyzer 100, a chemical condition, a physical property, a distance, and/or time. Still further, the channels optionally relate to radial distance between the incident light from the analyzer 100 entering skin of the subject 170 and detected light exiting the skin of the subject 170 and detected by the detector system 130, a focal length of an optic, a solid-angle of a photon beam from the source system 110, an incident angle of light onto skin of the subject, and/or a software setting, such as control over spectral resolution. For clarity of presentation, the channels are described herein in terms of wavelength channels. For example, a spectrum is collected over a range of wavelengths and the finite width channels represent finite width wavelength channels within the spectrum. Generally, the channels are processed to enhance localized signal, to decrease localized noise, and/or are processed using a cross-wavelet transform.

In one case, the sample property analysis system 1650 defines a plurality of finite width wavelength channels, such as more than 3, 5, 10, 15, 20, 30, 40, or 50 wavelength channels contained in a broader spectral region, such as within a spectrum from 900 to 2500 nanometers or within a sub-range therein, such as within 1100 to 1800 nanometers. The plurality of multiple finite width wavelength channels enhance accessibility to content related to: (1) a target analyte, such as a glucose concentration, and (2) a measurement context, such as the state of skin of the subject 170, which is used as information in a self-correcting background.

Feature Extraction

In one case, feature extraction determines and/or calculates coherence between channels, which is referred to herein as cross-coherence, to identify and/or enhance information common to the analytical signal, such as frequency, wavelength, shift, and/or phase information. Subsequently, cross-coherence terms are selected using a metric, such as to provide maximum contrast between: (1) the target analyte or signal and (2) the measurement context or background. Examples of background include, but are not limited to: spectral interference, instrument drift impacting the acquired signal, spectral variation resultant from physiology and/or tissue variation, temperature impact on the analyzer, mechanical variations in the analyzer as a function of time, and the like. Generally, the cross-coherence terms function to reduce toward or to monotonicity detected variation as a function of analyte concentration. In a particular instance, an N×N grid is generated per spectrum, which is symmetric about the diagonal of the N×N grid, with each grid element representing an M term coherence estimate versus frequency, where N is a positive integer of at least three.

Model

Typically, a model, such as a nonlinear model, is constructed to map the extracted features to the analyte property, such as a glucose concentration. For example, the total differential power of the cross-coherence estimate is determined between features related to the analyte versus the background and a separate nonlinear function is calculated for multiple analyte ranges.

Absorbance Spectra

The data processing system 140 optionally uses absorbance spectra of skin and/or blood constituents, such as water absorbance peaks at about 1450 nm or in the range of 1350 to 1500 nm.

Personal Communication Device

Herein, a personal communication device comprises any of a wireless phone, a cell phone, a smart phone, a tablet, and/or a wearable internet connectable accessory, a wearable internet connectable garment.

Still yet another embodiment includes any combination and/or permutation of any of the analyzer and/or sensor elements described herein.

The particular implementations shown and described are illustrative of the invention and its best mode and are not intended to otherwise limit the scope of the present invention in any way. Indeed, for the sake of brevity, conventional manufacturing, connection, preparation, and other functional aspects of the system may not be described in detail. Furthermore, the connecting lines shown in the various figures are intended to represent exemplary functional relationships and/or physical couplings between the various elements. Many alternative or additional functional relationships or physical connections may be present in a practical system.

In the foregoing description, the invention has been described with reference to specific exemplary embodiments; however, it will be appreciated that various modifications and changes may be made without departing from the scope of the present invention as set forth herein. The description and figures are to be regarded in an illustrative manner, rather than a restrictive one and all such modifications are intended to be included within the scope of the present invention. Accordingly, the scope of the invention should be determined by the generic embodiments described herein and their legal equivalents rather than by merely the specific examples described above. For example, the steps recited in any method or process embodiment may be executed in any order and are not limited to the explicit order presented in the specific examples. Additionally, the components and/or elements recited in any apparatus embodiment may be assembled or otherwise operationally configured in a variety of permutations to produce substantially the same result as the present invention and are accordingly not limited to the specific configuration recited in the specific examples.

Benefits, other advantages and solutions to problems have been described above with regard to particular embodiments; however, any benefit, advantage, solution to problems or any element that may cause any particular benefit, advantage or solution to occur or to become more pronounced are not to be construed as critical, required or essential features or components.

As used herein, the terms “comprises”, “comprising”, or any variation thereof, are intended to reference a non-exclusive inclusion, such that a process, method, article, composition or apparatus that comprises a list of elements does not include only those elements recited, but may also include other elements not expressly listed or inherent to such process, method, article, composition or apparatus. Other combinations and/or modifications of the above-described structures, arrangements, applications, proportions, elements, materials or components used in the practice of the present invention, in addition to those not specifically recited, may be varied or otherwise particularly adapted to specific environments, manufacturing specifications, design parameters or other operating requirements without departing from the general principles of the same.

Herein, a set of fixed numbers, such as 1, 2, 3, 4, 5, 10, or 20 optionally means at least any number in the set of fixed number and/or less than any number in the set of fixed numbers.

Although the invention has been described herein with reference to certain preferred embodiments, one skilled in the art will readily appreciate that other applications may be substituted for those set forth herein without departing from the spirit and scope of the present invention. Accordingly, the invention should only be limited by the Claims included below. 

1. An apparatus for noninvasively determining an analyte concentration of a subject, comprising: a near-infrared noninvasive vibrational spectroscopy analyzer, comprising: a sample interface; a photon transport system comprising at least one optic configured for at least one: transporting photons to an illumination zone proximate said sample interface; and collecting photons from a detection zone proximate said sample interface; a first two-dimensional detector array; a second two-dimensional detector array, both said first two-dimensional detector array and said second two-dimensional detector array positioned proximate at least one of the illumination zone and the detection zone; and a controller, of said analyzer, configured to receive simultaneously collected signals from both said first two-dimensional detector array and said second two-dimensional detector array, the signals used in calculation of the analyte concentration.
 2. The apparatus of claim 1, further comprising: a housing, said housing substantially enclosing all of said source, said photon transport system, and said first two-dimensional detector array, said first two-dimensional detector array comprising an m by n array of detector elements, wherein m and n comprise positive integers greater than four, wherein said photon transport system comprises optics directing photons along a z-axis to a sample region along an x,y-plane, the x,y-plane perpendicular to the z-axis, wherein said first two-dimensional detector array comprises a two-dimensional near-infrared detector array.
 3. The apparatus of claim 1, said first two-dimensional detector array and said second two-dimensional detector array positioned on opposite sides of a mean photon path center of the illumination zone.
 4. The apparatus of claim 1, said first two-dimensional detector array positioned along a first vector from a mean optical center of the illumination zone, said second two-dimensional detector array positioned along a second vector from the mean optical center of the illumination zone, said first vector and said second vector forming an angle between twenty and two hundred degrees.
 5. The apparatus of claim 1, said first two-dimensional detector array comprising a larger number of detectors than said second two-dimensional detector array.
 6. The apparatus of claim 1, said first two-dimensional detector array comprising a set of detectors comprising indium, gallium, and arsenide, said second two-dimensional detector array comprising at least one of a temperature sensor and a pressure sensor.
 7. The apparatus of claim 1, a center of said first two-dimensional detector array comprising a position along a vector from a center of said illumination zone, said first two-dimensional detector comprising at least one column of detectors rotated at least ten degrees off of the vector.
 8. The apparatus of claim 1, further comprising: an array of optics, individual optical elements of said array of optics respectively optically coupled to rows of detector elements of said two-dimensional detector array.
 9. The apparatus of claim 1, further comprising: a two-dimensional optical transmittance filter array, wherein a first filter of said two-dimensional optical transmittance filter array optically couples to a first line of detector elements of said two-dimensional detector array, wherein a second filter of said two-dimensional transmittance filter array optically couples to a second line of detector elements of said two-dimensional detector array, wherein, at at least one wavelength in the range of 1500 to 1800 nm, said first filter comprises a first filter transmittance differing from a second filter transmittance of said second filter by at least thirty percent.
 10. The apparatus of claim 1, said near-infrared noninvasive vibrational spectroscopy analyzer further comprising: a first optical filter comprising transmittance of at least sixty percent of light in a wavelength range of 1100 to 1350 nm and transmittance of less than twenty percent in a wavelength range of 1500 to 1750 nm, said first optical filter optically coupled to a first group of detectors of said two-dimensional detector array; and a second optical filter comprising transmittance of at least sixty percent of light in a wavelength range of 1500 to 1700 nm and transmittance of less than twenty percent in a wavelength range of 1100 to 1300 nm, said second optical filter optically coupled to a second group of detectors of said two-dimensional detector array.
 11. The apparatus of claim 1, said first two-dimensional detector array comprising: a first number of detectors in a first row; and a second number of detectors in a second row, said second number less than said first number.
 12. The apparatus of claim 1, further comprising: a first optical filter comprising a first transmittance profile; and a second optical filter comprising a second transmittance profile, the second transmittance profile different from said the first transmittance profile, wherein said first optical filter optically covers a first region of said first two-dimensional detector array, and wherein said second optical filter optically covers a second region of said first two-dimensional detector array.
 13. The apparatus of claim 1, said near-infrared noninvasive vibrational spectroscopy analyzer further comprising: a two-dimensional transmittance filter array in an optical path of said analyzer, comprising: a first filter comprising a first fifty percent cut-on transmittance inflection point at a first wavelength in a range of 1200 to 2500 nanometers; a second filter comprising a second fifty-percent cut-on transmittance inflection at a second wavelength, said second wavelength at least one hundred nanometers shorter than said first wavelength, said first filter positioned closer to the illumination zone than said second filter.
 14. The apparatus of claim 13, said two-dimensional transmittance filter array both substantially co-planar and in contact with said two-dimensional detector array.
 15. The apparatus of claim 13, further comprising: a two-dimensional near-infrared detector optic array, each element of said two-dimensional detector optic array optically coupled to at least one detector element of said two-dimensional detector array.
 16. A method for noninvasively determining an analyte concentration of a subject, comprising: providing a sample interface; using a photon transport system comprising at least one optic for at least one: transporting photons to an illumination zone proximate said sample interface; collecting photons from a detection zone proximate said sample interface; collecting a first set of signals using a first two-dimensional detector array; collecting a second set of signals using a second two-dimensional detector array, both said first two-dimensional detector array and said second two-dimensional array positioned in a common housing of a noninvasive vibrational spectroscopy analyzer proximate at least one of the illumination zone and the detection zone receiving, to a processor, the first set of signals and the second set of signals; and using the signals in calculation of the analyte concentration.
 17. The method of claim 16, further comprising the step of: positioning both said first two-dimensional detector array and said second two-dimensional detector array within ten centimeters of the subject during use of said analyzer.
 18. The method of claim 16, further comprising the steps of: using a first detector gain setting for a detector element of said first two-dimensional detector array; and simultaneously using a second detector gain setting for a detector element of said second two-dimensional detector array, said second gain setting at least ten percent larger than said first detector gain setting.
 19. The method of claim 16, further comprising the steps of: using a first integration time for a first detector of said first two-dimensional detector array; and using a second integration time for a second detector of said first two-dimensional detector array, said second detector positioned further from a center of said detection zone than said first detector, said second integration time at least ten percent larger than said first integration time.
 20. The method of claim 19, further comprising the steps of: using a first optical filter coupled to a first sub-set of detectors of said first two-dimensional detector array; and using a second optical filter coupled to a second sub-set of said first two-dimensional detector array, wherein a fifty percent cut-on wavelength of said first filter differs from a fifty percent cut-on wavelength of said second optical filter by at least two hundred nanometers.
 21. The method of claim 16, further comprising the steps of: communicating the signals to a personal communication device; using said personal communication device in a process of calculating the analyte concentration.
 22. The method of claim 16, further comprising the steps of: extracting spectroscopic features related to optical pathlength; and using said features in calculation of the analyte concentration. 